This proposal explores the balance between sympathetic vasoconstrictor activity and blood pressure regulation in younger and older humans. While baseline sympathetic nerve activity (MSNA) is stable in young normotensive males, there is wide inter-individual variation in baseline MSNA and no clear relationship between MSNA and arterial pressure. Additionally, sympathetic activity increases with normal aging but is not consistently associated with marked increases in arterial pressure. In this context, our recent studies suggest a balance among sympathetic activity, cardiac output, and vasoconstrictor responsiveness to adrenergic stimuli might explain how arterial pressure remains normal when baseline sympathetic activity is high. By exploring the following specific aims we test the overall hypotheses that high baseline sympathetic activity in normotensive younger and older subjects is balanced by reciprocal changes in cardiac output and vascular adrenergic responsiveness that limit the blood pressure raising impact of the sympathoexcitation. Specific Aim 1: We will test whether the reciprocal relationship between cardiac output (CO) and sympathetic nerve activity is disrupted by normal aging. We hypothesize that this relationship is not disrupted but that healthy older subjects have lower cardiac outputs and proportionally higher sympathetic activity than young subjects. Our secondary hypothesis is that women have a similar CO-MSNA relationship to men, but for any given CO, sympathetic activity is lower in women. A tertiary hypothesis is that baseline MSNA will not be related to 24 hour ambulatory blood pressure measurements. Specific Aim 2: We will test whether changes in blood volume and CO with normal aging are linked to the increase in MSNA by using volume expansion and lower body negative pressure to manipulate CO. We hypothesize that sympathetic activity will be similar at a given CO and arterial pressure in both older and younger subjects. Specific Aim 3: We will test whether a1- versus a2-adrenergic receptors are involved in the decreased vascular responsiveness seen in normotensive subjects with high MSNA. We hypothesize there will be an inverse relationship between baseline MSNA and vascular responsiveness that will be most obvious for a1-receptors in both younger and older subjects. We also propose exploratory analysis of genomic variation in a1- and a2-adrenergic receptors and related pathways from subjects with varying levels of baseline sympathetic activity. Specific Aim 4: We will test whether baroreflex control of MSNA is related to baseline MSNA and how this changes with aging. We hypothesize that subjects with high baseline MSNA will demonstrate blunted baroreflex control of MNSA. In summary, this overall approach will permit us to understand how normotensive is maintained in humans with high baseline sympathetic activity and set the stage for understanding how these mechanisms might fail in hypertension. [unreadable] [unreadable] [unreadable] [unreadable]